*Medians are similar; however, PFS curves part after the median as reflected by HR.

Significant differences in DCR, BORR, and PFS were observed.

For these outcomes, patients treated with ipilimumab alone did better than those treated with the combination, although both groups fared better than gp100 alone.

Severe adverse events tended to be immune-related GI toxicity (colitis and perforation) and occurred in 23% of Ipilimumab alone patients and 17% of patients treated with the combination.

Authors' Conclusions

Ipilimumab is the first agent to improve overall survival in a phase III study of previously treated patients with advanced melanoma.

The addition of gp100 vaccine to ipilimumab did not improve outcomes relative to ipilimumab alone, and actually led to inferior rates of secondary endpoint measures of disease control, best objective response, and progression-free survival. However, it did not affect overall survival rates or the safety profile.

Ipilimumab is a promising agent for immune modulation that should be explored in NSCLC and metastatic prostate cancer.

Clinical Implications

This exciting study is the first Phase III trial to demonstrate an overall survival benefit in previously treated patients with advanced melanoma - a particularly challenging group of patients.

The arm receiving gp100 vaccine alone appears to be an appropriate control group, when OS rates for this group are compared to those reported in a prior meta-analysis (Korn, JCO, 2008)

Therefore, the impressive OS advantage reported here can be assumed to be relative to standard first-line therapy.

In this study, ipilimumab alone appeared to be superior to the combination of ipilimumab and gp100 vaccine, which is intriguing because ipilimumab (unlike gp100 vaccine) is not specific to melanoma, but rather acts upon the immunomodulatory molecule CTLA-4;

This suggests that ipilimumab may in fact have activity in a number of different types of cancer that are effective at evading immune surveillance.

Therefore, it would be justified to explore the clinical utility of this antibody in other sites of metastatic disease that are refractory to current therapies.

Unanswered questions:

This study included only HLA-A*0201 positive patients (because gp100 peptide is HLA-A2 restricted); in the future, if gp100 is excluded from this treatment regimen, which patients would be considered eligible for treatment?

The dose of ipilimumab used in this study (3 mg/kg) was outperformed in a previous dose finding study by the 10 mg/kg dose, so it is unclear if this study used the optimal dose and scheduling of the drug.

The control used in this study (gp100 vaccine) is questionable, because there is no standard of care for salvage after first line treatment in advanced melanoma.

Ipilimumab is a potent activator of the immune system, and safe treatment requires aggressive surveillance in order to recognize serious adverse events; this may not be feasible in a community setting.

The question of whether ipilimumab may have a role as part of adjuvant treatment for resected melanoma remains outstanding.

In sum, ipilimumab is the first agent to improve overall survival of patients with advanced melanoma in a Phase III trial, and has an intriguing mechanism of action that may be applicable across different disease sites. Nevertheless, at this time the treatment of choice for patients with advanced melanoma remains a clinical trial, as several questions remain unanswered about how best to integrate this agent into clinic practice.